CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma.
Fiche publication
Date publication
juillet 2021
Journal
EMBO reports
Auteurs
Membres identifiés du Cancéropôle Est :
Dr COIN Frédéric, Dr DAVIDSON Irwin, Dr EGLY Jean-Marc, Dr COMPE Emmanuel
Tous les auteurs :
Berico P, Cigrang M, Davidson G, Braun C, Sandoz J, Legras S, Vokshi BH, Slovic N, Peyresaubes F, Gene Robles CM, Egly JM, Compe E, Davidson I, Coin F
Lien Pubmed
Résumé
Melanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal-like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic-type melanoma cells into mesenchymal-like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7. In addition to emergence of a mesenchymal-type signature, we identify a GATA6-dependent gene expression program comprising genes such as AMIGO2 or ABCG2 involved in melanoma survival or targeted drug tolerance, respectively. Mechanistically, we show that CDK7 drives expression of the melanocyte lineage transcription factor MITF that in turn binds to an intronic region of GATA6 to repress its expression in melanocytic-type cells. We show that GATA6 expression is activated in MITF-low melanoma cells of patient-derived xenografts. Taken together, our data show how the poorly characterized repressive function of MITF in melanoma participates in a molecular cascade regulating activation of a transcriptional program involved in survival and drug resistance in melanoma.
Mots clés
CDK7, GATA6, MITF, TFIIH, melanoma
Référence
EMBO Rep. 2021 Jul 23;:e51683